Background Information
Cancer of the uterus is the most common cancer of the female reproductive tract and the fourth most common cancer among women in the United States. About 35,000 new cases of endometrial cancer are diagnosed in the United States each year. In 2000, an estimated 6500 women will die of the disease (American Cancer Society statistics). The racial and ethnic diversity of endometrial cancer follows a pattern similar to that of breast cancer. Women with the highest age-adjusted incidence of endometrial cancer in the SEER areas include Hawaiians, whites, Japanese, and blacks. The lowest rates occur among Korean, Vietnamese, and American Indian women.
The most common type of cancer of the uterus develops in the glandular cells or endometrium, the lining inside of the uterine cavity. This is the same tissue that is shed each month during a normal menstrual period. This type of cancer is called endometrial or uterine cancer. A small number of endometrial cancers (3%) are sarcomas, which grow in the muscular and connective tissue elements of the uterus. As uterine cancer grows, it may invade nearby organs. Uterine cancer cells also may break away from the tumor and spread to other parts of the body, such as the lungs, liver, and bones.
Currently, there are no screening tests for uterine cancer which are recommended on a routine basis other than yearly pelvic examination. The focus in this cancer is on prevention by avoiding excessive estrogenic stimulation of the uterine lining due to obesity, hormone replacement or other factors (National Comprehensive Cancer Network). If a patient is found with local disease (cancer confined entirely to the uterus), the five-year survival rate is observed to be 95%. As the disease progresses to regional (malignant cancer that has extended beyond the limits of the uterus directly into surrounding organs, tissues, or lymph nodes), the five-year survival rate decreases to 64%. If the disease is found to be distant (malignant cancer that has spread to parts of the body remote from the uterus), the five-year survival rate is lowest at only 25% (American Cancer Society, Surveillance Research).
The most common symptom of uterine cancer is abnormal vaginal bleeding, especially after menopause. Other symptoms include difficult or painful urination, pain during intercourse, or pain in the pelvic area. These symptoms are not diagnostic for cancer however, and further examination is necessary. Follow-up with a physician may involve a pelvic exam, a pap test, or a biopsy. A biopsy is necessary for diagnosis. No tumor markers for uterine cancer are known to date. Diagnosis is made by an H&E stain of the biopsy specimen. As has been shown with other cancers, diagnosis by histology is not as sensitive as diagnosis using tumor markers, either by immunohistochemical techniques, molecular techniques, or immunoassay. Improvement in the detection, diagnosis, staging, monitoring, and prognostication of uterine cancer can improve the survival rate of the patient.
The choice of treatment depends on the size of the tumor, the stage of the disease, whether female hormones affect tumor growth, and tumor grade. The tumor grade tells how closely the cancer resembles normal cells and suggests how fast the cancer is likely to grow. Low-grade cancers are likely to grow and spread more slowly than high-grade cancers.
Most women with uterine cancer are treated with surgery. Some have radiation therapy. A smaller number of women may be treated with hormone therapy or chemotherapy. Surgery to remove the uterus (hysterectomy) and the fallopian tubes and ovaries (bilateral salpingo-oophorectomy) is the treatment recommended for most women with uterine cancer. It is important to remove the ovaries during surgery because this represents one area where endometrial cancer may spread. Often, involvement of the ovaries with endometrial cancer cannot be observed by casual inspection during surgery and will only become apparent after removal when the pathologist looks at them under the microscope. Lymph nodes from the pelvic and lower aortic areas may also be removed during surgery to look for spread of the cancer, since this is the most common route of spread. If cancer has reached the lymph nodes, it may mean that the disease has spread to other parts of the body. If cancer cells have not spread beyond the endometrium, the disease can usually be cured with surgery alone.
After hysterectomy, additional treatment with radiation and/or chemotherapy is required in only a minority of cases in which spread of disease outside the uterus has been found or is suspected. Radiation therapy may be applied with an implant placed directly is into or near the tumor site (internal radiation) or be applied externally. Radiation therapy may be used in addition to surgery to treat women with certain stages of uterine cancer. Radiation may be used before surgery to shrink the tumor or after surgery to destroy any cancer cells that remain in the area.
Hormone therapy may be given to women who are unable to have surgery. This form of treatment is often recommended for women who have metastatic or recurrent endometrial cancer. Chemotherapy is also an option for patients with uterine cancer that has spread. Accurate staging and prognostication of the disease is critical to choosing optimal therapy.
Known risk factors include age (cancer of the uterus is most common in women over age 50); endometrial hyperplasia (women who have endometrial hyperplasia have a higher risk of developing uterine cancer); estrogen replacement therapy (women who use ERT to control symptoms associated with menopause, to prevent osteoporosis or to reduce the risk of heart disease or stroke may have an increased risk of uterine cancer. Long-term treatment and large doses seem to increase this risk. Using a combination of estrogen and progesterone decreases the risk linked to the use of estrogen alone. The progesterone protects the endometrium from the cancer-causing effect of estrogen); obesity (fat converts certain hormones into a form of estrogen. Women with excess fat produce higher levels of estrogen); diabetes and high blood pressure; and tamoxifen (an increased risk of developing uterine cancer has been found in women taking tamoxifen for the treatment of breast cancer. This risk may be related to the estrogen-like effect of this drug on the uterus). Other risk factors for uterine cancer are also related to estrogen, including having few or no children or entering menopause late in life. Some studies of women who have used oral contraceptives that combine estrogen and progesterone show that these women have a lower than average risk of uterine cancer.
The key risk factor for uterine cancer is estrogen, a hormone that occurs naturally in all women. Prevention of the disease by elimination of estrogen is not foreseeable. It therefore would be advantageous to provide specific methods and reagents useful for detecting, diagnosing, staging, monitoring, prognosticating, in vivo imaging, preventing, treating, or determining predisposition to diseases of the uterus. Such methods would include assaying a test sample for products of a gene(s) which are overexpressed in diseases and conditions associated with the uterus, including cancer. Such methods may further include assaying a test sample for products of a gene(s) whose distribution among the various tissues and compartments of the body have been altered by a uterus-associated disease or condition, including cancer. Such methods would comprise making cDNA from mRNA in the test sample, amplifying, when necessary, portions of the cDNA corresponding to the gene or a fragment thereof, and detecting the cDNA product as an indication of the presence of the disease or condition including cancer or detecting translation products of the mRNAs comprising gene sequences as an indication of the presence of the disease. Useful reagents include polynucleotides(s), or fragment(s) thereof which may be used in diagnostic methods such as reverse transcriptase-polymerase chain reaction (RT-PCR), PCR, or hybridization assays of mRNA extracted from biopsied tissue, blood, or other test samples; or proteins which are the translation products of such mRNAs; or antibodies directed against these proteins. Such assays would include methods for assaying a sample for product(s) of the gene and detecting the product(s) as an indication of disease of the breast. For example, these assays would include methods for detecting the gene products (proteins) in light of possible post-translational modifications that can occur in the body. Such post-translational modifications can include proteolytic processing, alteration of the chain termini, glycosylation, lipid attachment, sulfation, gamma-carboxylation, hydroxylation, phosphorylation, ADP-ribosylation, disulfide bond formation, and multiple non-covalent interactions with molecules such as co-factors, inhibitors (both small molecule and protein), activators (both small molecule and protein), and other proteins in formation of multi-subunit complexes. See, for example, T. E. Creighton et al., In: Proteins: Structures and Molecular Properties, Second Edition, pp. 78-102, New York, N.Y.: W. H. Freeman and Co. 1993.
Drug treatment or gene therapy for diseases and conditions of the uterus including cancer can be based on these identified gene sequences or their expressed proteins, and efficacy of any particular therapy can be monitored. Furthermore, it would be advantageous to have available alternative, less-invasive diagnostic methods capable of detecting early stage uterine disease, such as cancer.
All U.S. patents and publications referred to herein are hereby incorporated in their entirety by reference.